促进细胞凋亡的肿瘤发生：γ 射线诱导的胸腺淋巴瘤发生需要 Puma 驱动的白细胞死亡。
Apoptosis-promoted tumorigenesis: gamma-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death.
机构信息
The Walter and Eliza Hall Institute of Medical Research, Parkville VIC 3050, Australia.
出版信息
Genes Dev. 2010 Aug 1;24(15):1608-13. doi: 10.1101/gad.1940110.
Abstract
Although tumor development requires impaired apoptosis, we describe a novel paradigm of apoptosis-dependent tumorigenesis. Because DNA damage triggers apoptosis through p53-mediated induction of BH3-only proteins Puma and Noxa, we explored their roles in gamma-radiation-induced thymic lymphomagenesis. Surprisingly, whereas Noxa loss accelerated it, Puma loss ablated tumorigenesis. Tumor suppression by Puma deficiency reflected its protection of leukocytes from gamma-irradiation-induced death, because their glucocorticoid-mediated decimation in Puma-deficient mice activated cycling of stem/progenitor cells and restored thymic lymphomagenesis. Our demonstration that cycles of cell attrition and repopulation by stem/progenitor cells can drive tumorigenesis has parallels in human cancers, such as therapy-induced malignancies.
摘要
虽然肿瘤的发展需要凋亡功能受损，但我们描述了一种新的依赖于凋亡的肿瘤发生模式。由于 DNA 损伤通过 p53 介导的 BH3 仅蛋白 Puma 和 Noxa 的诱导引发凋亡，我们研究了它们在γ射线诱导的胸腺淋巴瘤发生中的作用。令人惊讶的是，虽然 Noxa 的缺失加速了肿瘤的发生，但 Puma 的缺失则使肿瘤发生完全消除。Puma 缺失的肿瘤抑制作用反映了它对白细胞免受γ辐射诱导死亡的保护作用，因为在 Puma 缺陷小鼠中，糖皮质激素介导的白细胞耗竭激活了干细胞/祖细胞的循环，并恢复了胸腺淋巴瘤的发生。我们的研究表明，由干细胞/祖细胞的细胞损耗和再增殖循环可以驱动肿瘤发生，这与人类癌症（如治疗诱导的恶性肿瘤）存在相似性。
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本文引用的文献
1
Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation.急性 DNA 损伤诱导白细胞凋亡促进淋巴瘤形成。
Genes Dev. 2010 Aug 1;24(15):1602-7. doi: 10.1101/gad.1940210.
2
Deletion of proapoptotic Puma selectively protects hematopoietic stem and progenitor cells against high-dose radiation.凋亡促进蛋白 Puma 的缺失选择性地保护造血干细胞和祖细胞免受大剂量辐射。
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Irradiation selects for p53-deficient hematopoietic progenitors.辐照选择缺乏 p53 的造血祖细胞。
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Deletion of Puma protects hematopoietic stem cells and confers long-term survival in response to high-dose gamma-irradiation.Puma 的缺失可保护造血干细胞，并赋予其在大剂量 γ 射线辐射下的长期存活能力。
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Cancer-related inflammation.癌症相关炎症
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Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis.在Myc驱动的B细胞淋巴瘤发生过程中对PUMA基因表达的选择抑制
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